Is TLE6 p.Val273Ile (c.817G>A) pathogenic?

TLE6 p.Val273Ile (c.817G>A) is classified Uncertain significance in TLE6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-14). AlphaMissense: likely benign (0.0746); Very rare (popmax 0.00833%, amr).

How common is TLE6 p.Val273Ile (c.817G>A) in the general population?

TLE6 p.Val273Ile (c.817G>A) is very rare (popmax 0.00833%, amr) (gnomAD).

What do computational predictors say about TLE6 p.Val273Ile (c.817G>A)?

AlphaMissense predicts likely benign (score 0.0746) — an in-silico prediction, not a clinical call.

TLE6 p.Val273Ile

c.817G>A · VCV4595437

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0746 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0746	likely benign
REVEL	0.005	strongly benign-leaning
SaProt	LLR -6.11	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -6.7
Regional constraint	o/e 1.13	unconstrained · MANE · 17 kb · p 0.00048 · regional, not allelic
Overall
CADD	0.053	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00833% Admixed American · 5/60,016 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00206%

Overall 0.00105% 17/1,614,134 alleles · very rare exomes 15/1,461,790 · genomes 2/152,344 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00833%	12,003
African / African-American	0.004%	25,023
East Asian	0.00223%	44,884
South Asian	0.0022%	45,544
Remaining individualsnot grpmax-eligible	0.0016%	62,510
European (non-Finnish)	0.000424%	236,008

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: TLE6
Protein: p.Val273Ile
Coding: c.817G>A
MANE Select: NM_001143986
Type: single nucleotide variant
Location: chr19:2989137 (GRCh38)
Gene constraint: LOEUF 1.121 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.29 · 4 PDB
Residue 273: an α-helix

Full TLE6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TLE6 p.Ala207Thr Uncertain significance ★★ ⚠ same type
TLE6 c.1537+7G>A Benign ★★ same type
TLE6 p.Glu287= Likely benign ★★ same type
TLE6 p.His285= Benign ★★ same type
TLE6 p.His564= Benign/Likely benign ★★ same type
TLE6 p.Ser490= Benign ★★ same type
TLE6 p.Val429= Benign ★★ same type
TLE6 c.741-1G>C Likely pathogenic ★ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/tle6-p-val273ile (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown